Luotonin A compound and preparation method and application thereof
A compound and reaction technology, applied in the field of Luotonin A series compounds and their preparation, can solve the problems of no clinical application value, low binding ability, low anti-tumor activity, etc., and achieve easy synthesis and preparation, stable structure, and strong anti-proliferation activity Effect
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[0058] Concrete preparation process comprises: compound shown in formula (1) and 2-methylquinoline-3-formic acid ethyl ester in I 2 / TsOH / DMSO system was heated and stirred at 110°C. After the reaction was completed, water was added to precipitate a solid, and the solid was hydrolyzed in alkaline water to obtain the compound represented by formula (2). Under the catalysis of DMF, the compound represented by formula (2) was converted into an acid chloride intermediate with oxalyl chloride, tetrahydrofuran was added after the reaction solvent was removed under reduced pressure, and sodium borohydride was added for reduction to obtain the compound represented by formula (3). The compound represented by formula (3) is subjected to Mitsunobu reaction with triphenylphosphine / diisopropyl azodicarboxylate in dichloromethane to obtain the compound represented by formula (4). The compound shown in formula (4) reacts with amine raw materials in N-methylpyrrolidone by heating to obtain th...
Embodiment 1
[0075] (1) Preparation of 2-(6,7-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)quinoline-3-carboxylic acid
[0076]
[0077] 2-Amino-4,5-difluorobenzamide (1.72g, 10mmol), ethyl 2-methylquinoline-3-carboxylate (2.28g, 12mmol), iodine (254mg, 1mmol) and p-toluenesulfonate Acid (1.72g, 10mmol) was dissolved in 20mL of DMSO and reacted at 110°C for 3h. After the reaction was completed, it was dropped into a saturated aqueous solution of sodium sulfite while hot, and a large amount of solid was precipitated. After filtering, the filter cake was dissolved in 50mL of methanol, and 4g of hydrogen was added. Sodium oxide solid, react at 50°C for 15min, after the reaction, distill methanol off under reduced pressure, add water and ethyl acetate, separate the layers, wash the water layer twice with ethyl acetate, pour it into a beaker, and use 10% Adjust the pH to 3-4 with hydrochloric acid, a large amount of solids precipitated, filtered, and dried to obtain 2.5 g of a light yellow sol...
Embodiment 2
[0091] Prepare the compound shown in formula (LX2) according to the method similar to Example 1 8-(1,4-Homopiperazin-1-yl)- 9-fluoroquinolino[2',3':3,4]pyrrolo[2,1-b]quinazolin-11(13H)-one , the yield is 40%,
[0092]
[0093] Its NMR carbon spectrum data are:
[0094] 1 H NMR (CDCl 3 ,600MHz)δ=8.35(d,J=37.6Hz,2H),7.97–7.69(m,3H),7.61(s,1H),7.41–7.19(m,1H),5.22(s,2H),3.68 (s,4H),3.14(s,2H), 2.96(s,2H),2.01(s,2H). 13 C NMR (CDCl 3 ,150MHz)δ=159.59,152.49(d,J=247.9Hz),152.42,151.46,149.38,147.68,144.82(d,J=9.0Hz),131.41, 130.64,130.55,129.60,128.72,128.391,127 (d, J=4.4Hz), 112.67 (d, J=25.4Hz), 111.63 (d, J=9.0Hz), 54.80, 51.14, 49.48, 48.26, 47.20, 30.78.
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